Pneumonia Clinical Trial
Official title:
Randomized Controlled Trial of Vitamin D Supplementation on Improvement of Pneumonic Children at Tertiary Pediatric Hospital in Egypt
In Egypt, according to UNICEF 2018, Acute Respiratory Tract Infection (ARTIs)was estimated to
account for 11% and 19% of the under-five and post-neonatal mortalities respectively.
Despite the well-recognized role of vitamin D in metabolism and homeostasis in the general
population, there is now growing interest in its probable association with pneumonia.
Globally, about 30% to 90% of Under-5 children experience vitamin D deficiency. This could
vary among children, according to the socioeconomic, environmental and behavioral
circumstances.
Studies evaluating the association of 1,25 (OH)2D deficiency and the severity of respiratory
tract infection, are rare and showed controversial findings.
However, an Indian systematic review polled the results of 12 studies, with 2279
participants, highlighted the significant correlation between vitamin D deficiency and
incidence and severity of ALRIs.
A prospective cohort study conducted in Yemen examined the ability of deficient levels of
vit.D to predict the outcomes of severe pneumonia. The study documented the significant
association between vitamin D deficiency with neutropenia and hypoxia in patients with severe
pneumonia, thus predicting the poor prognosis.
In Egypt 2010, a case-control study conducted on children aged 2 to 5 years to examine the
impact of vitamin D deficiency on the susceptibility of pneumonia. The study illustrated that
Vitamin D deficiency is associated with a higher incidence and more severe pneumonia.
Recent studies advocated providing children(particularly suffering from pneumonia) with
adequate amounts of vitamin D supplements.
Nevertheless, few studies have been conducted to evaluate the impact of vitamin D
supplementation on the outcome of pneumonic infants.
Thus, we urge to conduct a randomized controlled trial (RCT) in Abou ElReesh tertiary
Pediatric hospital, to evaluate the effects of vitamin D3 supplementation to children with
pneumonia. We postulated that supplementation of 100 000 IU of vitamin D3 (Cholecalciferol)
will reduce the duration of illness in those children and improve their outcome.
Subjects and Methods:
Study design and study setting The current study is a randomized, double-blinded
placebo-controlled trial (RCT) that was conducted in Cairo University Abou ElReesh Children
hospital, which is a university-affiliated teaching hospital in Egypt, to evaluate the effect
of vitamin D3 supplementation on the outcome of treatment of children with pneumonia.
Pneumonia cases were recruited from two of the hospital general pediatric departments and the
four pediatric intensive care units (PICUs) of the hospital.
Sample Size and study population To detect a 20% difference in the mean duration of pneumonia
between the vitamin D arm and control arm [5 days vs. 6 days (SD 2)] allowing Type I error of
5% and Type II error of 10%, 86 per group (172 total) is the minimum number to be recruited.
After allowing for 10% for nonresponse or loss for follow-up and 25% for the exclusion of
children diagnosed with sufficient or toxic level of vitamin D after vitamin D testing (Box
1) according to the prevalence of vitamin deficiency in a pediatric hospital of eastern
India, 233 was the minimum number to start with.
Mild and moderate pneumonia cases were recruited from two of the hospital general pediatric
departments chosen by a simple random sample from a total of six hospital departments while
severe pneumonia cases were recruited from the four PICUs of the hospital.
All children (259 children) between 1 month and 12 years of age admitted to the selected
departments during the period from 9th September 2019 to 15th December 2019 and diagnosed
clinically with pneumonia according to the World Health Organization criteria of severity
(Box 2) were screened for the inclusion criteria. Children who had clinical signs of rickets
(2 children), severe illnesses (meningitis, heart or renal disorders, measles, severe
malnutrition, endocrine dysfunction, hypercalcemia, hyperthyroidism, and suspected
tuberculosis) (4 children) or were known to have received high-dose vitamin D treatment in
the past 3 months (3 children) were excluded from the study. Children with sufficient (52
children) or toxic (7 children) levels of vitamin D were also excluded.
Thus, 191 child (93 in the intervention arm and 98 in the control arm) who had pneumonia with
insufficient or deficient level of vitamin D and their parents consented to participate were
enrolled in the study, completed the baseline and the outcome assessments and continued the
daily clinical follow up till their discharge (improvement or death) from the hospital.
Box 1: Level of vitamin D Sufficient vitamin D (25(OH)D: ≥ 30 ng/mL), Insufficient vitamin D
(25(OH)D or at risk of deficiency: 10-29 ng/mL), and Deficient vitamin D (25(OH)D: <10 ng/
mL).
Box 2: Diagnosis of Pneumonia Pneumonia: (i) Age-specific tachypnoea (>60 ⁄ min if <2 months;
>50 ⁄ min if 2-11 months; >40 if 12-24 months) and (ii) absence of wheeze (with or without
fever).
Fever: Axillary temperature >37.50 _C (age 1 week- 3 months) or >38.0 _C (2-23 months).
axillary temperature was measured using a standard mercury thermometers Respiratory rate was
measured twice for one full minute while the child is quiet using stopwatches taking the
average count.
Mild pneumonia: Minimally increased work of breathing, no hypoxemia, able to tolerate PO
Moderate pneumonia: Hypoxemia, inability to tolerate PO, moderately increased work of
breathing (grunting, retracting, tachypnea).
Severe Pneumonia: Significantly increased work of breathing, altered mental state, concern
for respiratory failure sepsis, failure to maintain oxygen saturation with Fi02 of 50%, need
for positive pressure ventilation. Oxygen saturation was measured using a pulse oximeter with
a probe on a finger or toe, in-room air.
Improvement (discharge criteria): (Meets all) tolerating PO, not hypoxemic (more than 90%),
mildly increase or normal work of breathing.
Vitamin D testing Two milliliters of venous blood was collected on plain tubes, left for 10
min to clot and then centrifuged at 3000 rpm for 5 min; the separated serum samples were
stored at -20 °C till the time of assay and used for detection of concentrations of serum
25OH Vitamin D Total ( 25OH Vitamin D2 and D3) by ELISA using (DIAsource 25OH Vitamin D Total
ELISA Kit, Catalogue No. KAP 1971) supplied by DIA source Immunoassays S.A. (Rue Du Bosquet,
2 B-1348 Louvain-la Neuve, Belgium ), according to the manufacturer's instructions and based
on the principle of solid-phase Enzyme-Linked Immunosorbent Assay performed on microtiter
plates. The amount of substrate turnover is determined colorimetrically by measuring the
absorbance, which is inversely proportional to the total 25OH Vitamin D (D2 and D3)
concentration. A calibration curve is plotted and the total 25OH Vitamin D (D2 and D3)
concentrations of the samples are determined by dose interpolation from the calibration
curve.
Random allocation of study groups The children were individually randomized into intervention
or control groups using a random number sequence elicited in an Excel spreadsheet with no
limitations. The allocation was further hidden by using closed dark envelopes. A
biostatistician and an office secretary who were not members of the investigating team did
independently the randomization, repackaging, sequencing, and allocation concealment. None of
the study staff and participants' parents were aware of the drug or placebo being dispensed.
The codes were revealed only at the time of final data analysis.
The children were followed clinically on a daily base by the three study pediatricians to
assess the resolution or deterioration of signs and symptoms of pneumonia till being
discharged from the hospital whether due to recovery or death. The routine treatment of
inpatient children is free of charge in Abou ElReesh Children's hospital, while vitamin D was
paid by the researchers to be given free of charge to the children in the intervention arm
during the study period.
Baseline assessment Data was collected for each participant regarding socio-demographic
variables (age, sex, feeding practices), skin color, nature and duration of presenting
symptoms. All children were examined for vital signs (temperature, heart rate, respiratory
rate, blood pressure, oxygen saturation), pallor, cyanosis, nasal flaring, grunt, and mental
status. Pa O2/FIO2 was measured and serum creatinine, C reactive protein, platelet count and
serum bilirubin laboratory tests were done. SOFA score was assessed for severe pneumonia
cases.
Intervention All children were treated with antibiotics according to WHO classification and
treatment of childhood pneumonia at health facilities 2012, at enrollment after obtaining
consent from parents and completing the baseline assessment, children were given a single
injection of one ml of 100.000 IU of vitamin D3 (Cholecalciferol), vitamin D3 obtained from 2
ml vials containing 200,000 IU each (Devarol- S- 200.000 I.U. produced by Memphis. for
Pharmaceutical and Chemical Industries) and stored in manufacturer's recommended conditions
in a dry, cool environment for 1-16 weeks (depending on the date of recruitment) or placebo
which is 1 ml saline injection. Syringes were labeled with a unique ID number and given by
the blinded doctors choosing the next syringe with a randomization code. (only office
secretary aware of randomization codes).
Hospital follow-up Children were monitored with recording data every eight hours for
respiratory rate, chest indrawing, oxygen saturation, auscultation findings, fever, feeding,
cyanosis, and mental status. The child was discharged when fever and fast breathing were
absent for 2 consecutive days.
Outcomes assessment Outcomes were assessed 7 days after vitamin D injection, the first day
whereas vitamin D reaches its maximum level in the blood to guarantee the assessment of all
participants before their discharge. The primary outcome variables were changed in serum
level of 25(OH)D, PaO2/FIO2, serum creatinine, C reactive protein, and serum bilirubin levels
and platelets count. Also, the SOFA score for severe cases. The secondary outcomes included
the fate of the cases (improvement or death) and the duration between enrolment and hospital
discharge for improved cases.
Statistical analysis:
Patients' percent change of Vitamin D (25 (OH)2D) was calculated to quantify the change
levels before and after vitamin D3 (Cholecalciferol) administration through the equation:
Pediatric, Blood Vitamin D level (BVD) %change = [(BVD after - BVD before) ÷ BVD before] ×
100 Collected data were entered and analyzed using the Statistical Package for Social Science
Software (SPSS) program, version 21.0 IBM. Tests of normality of data (like Shapero-Wilk
test) revealed that data isn't normally distributed. That's why non-parametric tests like
Mann-Whitney and Kruskal-Wallis tests were used in univariable comparisons to quantify the
associations of continuous variables. Data were summarized using the median and interquartile
range for quantitative variables. Spearman correlation test was used to detect the
relationship between continuous variables. P values below 0.05 were considered statistically
significant. A multivariate Cox regression analysis model was conducted to explore the
independent effect of vitamin D3 supplementation on the overall survival of pneumonic
children.
Given the short period of the study follow-up and single intervention, there was no stopping
rule or interim analyses.
All children randomized were included in the analysis on an intention-to-treat basis unless
the outcome measures were missing (n = 0) or reported to have recovered or lost within 24 h
(n = 0). Meantime to recovery for the episode of pneumonia at recruitment was compared for
the vitamin D group and control group. Kaplan-Meier plots and log-rank tests were used to
compare the time to recover from the index episode of pneumonia between the vitamin D and
placebo groups.
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